Community-Acquired MRSA: Update on Epidemiology, Treatment, and Prevention John S. Bradley, MD, FAAP Infectious Disease

1. TM Prepared for your next patient. Community-Acquired MRSA: Update on Epidemiology,Treatment, and Prevention John S. Bradley, MD, FAAP Infectious Diseases Division University of California, San Diego Rady Children’s Hospital San Diego

2. Disclaimers • Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics. • Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenter has complete and independent control over the planning and content of the presentation, and is not receiving any compensation from Mead Johnson for this presentation. The presenter’s comments and opinions are not necessarily those of Mead Johnson.  In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications,  Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label.

3. CA-MRSA Epidemiology Pathogenicity Clinical Presentation Treatment (New Guidelines) Prevention

4. Epidemiology:Virulent CA-MRSA First clinical reports in the US appeared about 10 years ago Likely to have emerged several times in the past (many different clones described, but only a few have been successful over time)…still evolving! May now be losing methicillin-resistance genes, but still virulent!!

5. CA-MRSA • Differs in clinical disease compared with MSSA and past hospital-acquired MRSA strains • Uniformly resistant only to beta-lactam antibiotics (penicillins, cephalosporins, carbapenems)* • Variably resistant to macrolides and to lincosamides (clindamycin) *Except ceftaroline, just approved by FDA for adults in October 2010.

6. CA-MRSA:Primary PFGE type: USA 300 (CDC) Methicillin-resistance cassette associated with CA-MRSA Deurenberg RH, Vink C, Kalenic S, et al. The molecular evolution of methicillin-resistant Staphylococus aureus. Clin Microbiol and Infect. 2006;13(3):222-235. SCCmec types (Staphylococcal Chromosome Cassette)

7. Kobayashi SD, DeLeo FR. An update on community-associated MRSA virulence. Curr Opin Pharmacol. 2009;9(5):545-551. Increased virulence in CA-MRSA USA 300 appears to be linked to virulence factors OR Alterations in gene Regulation Phenol soluble modulins Panton-Valentine leukocidin α-hemolysins Arginine catabolic mobile element (ACME) agr (accessory gene regulator)

8. Kobayashi SD, DeLeo FR. An update on community-associated MRSA virulence. Curr Opin Pharmacol. 2009;9(5):545-551. CA-MRSA: PMN Killing Following Phagocytosis

9. Saline control in lungs Staph without PVL Staph with PVL Subsequently found to be a dysregulated PVL hyperproducer. Labandeira-Rey M, Couzon F, Boisset S, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315(5815):1130-1133. CA-MRSA: Mouse Lung Infection Model

10. PVL PVL Labandeira-Rey M, Couzon F, Boisset S, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315(5815):1130-1133. CA-MRSA: Necrotizing Pneumonia

11. CA-MRSA: What it Does CA-MRSA appears to cause deeper, more invasive infections than MSSA CA-MRSA appears to cause necrotizing fasciitis at a greater rate than MSSA CA-MRSA does not appear to cause bacteremic disease more frequently CA-MRSA appears to cause recurrent infections more frequently

12. CA-MRSA CA-MRSA appears to have a selective advantage in the community, and represents an increasing proportion of staph responsible for hospitalizations, just like penicillin-resistant strains did over 30 years ago In many regions of the USA, rates of MRSA have stabilized at 40-90% (we don’t know why rates vary)

13. All children with abscesses (n = 69) The “spider bite” Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J.2004;23(2):123-127. Clinical Characteristics and Management Dallas, Texas

14. Complicated MRSA Pneumonia Enhanced Destruction of Lung with Influenza Co-infection

15. Complicated MRSA Pneumonia Late Fibrosis

16. Cellulitis (short arrow) Panniculitis (long arrow) Fasciitis (arrowhead) Gram-positive cocci in clusters (arrow) Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Eng J Med. 2005;352(14):1445-1453. Necrotizing Fasciitis with MRSA

17. CA-MRSA in Pediatrics

18. 2 weeks post skin grafting [But no Necrotizing Fasciitis since in SD in 3 years] CA-MRSA in Pediatrics

19. CA-MRSA: Complication Rates This is not the old Staph: all of the information/publication/experience regarding the old MSSA strains may not apply to CA-MRSA Complication rates are higher and response to treatment is slower; inflammation and induration may not be resolved by 10-14 days

20. CA-MRSA: Diagnosis • Cultures are important for all presumed staph infections as many are still MSSA • Rapid tests are now available • From cultured organisms: latex particles coated with monoclonal antibody to PBP 2a • PCR from colonized anatomic sites, looking for the mecA methicillin resistance genes

21. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. IDSA Guidelines for CA-MRSA Endorsed by the AAP January 2011

22. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Community-Acquired Pneumonia (CAP) • For children hospitalized with severe CAP empiric therapy for MRSA is recommended (pending sputum and/or blood culture results): • Those requiring an intensive care unit (ICU) admission, OR • Necrotizing or cavitary infiltrates, OR • Empyema • Vancomycin recommended for children • If the patient is stable without ongoing bacteremiaor intravascular infection, clindamycin can be usedas empirical therapy if the clindamycin resistance rate is low (eg, 10%) • Linezolid is an alternative [watch for more data on this issue]

23. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Adjunctive Therapy for MRSA • Not routinely recommended: Protein synthesis inhibitors (eg, clindamycin and linezolid) and intravenous immunoglobulin (IVIG) • Some experts may consider these agents in selected scenarios (eg, necrotizing pneumonia or severe sepsis)

24. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Vancomycin Dosing for Children • Vancomycin 15 mg/kg/dose every 6 h (60 mg/kg/day) is recommended for serious or invasive disease (data are limited to guide vancomycin dosing in children). • Trough concentrations of 15–20 mcg/mL should be considered in those with serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (eg, necrotizing fasciitis) • The efficacy and safety of this dose requires additional study • [AUC:MIC > 400]

25. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Treatment for Skin / Skin Structure Infections (SSTI) • Hospitalized children with complicated SSTI: • Vancomycin • Clindamycin is an option if the patient is stable, without ongoing bacteremia or intravascular infection, and if the clindamycin resistance rate is low (eg,10%); allows transition to oral therapy • Linezolid is an alternative

26. CA-MRSA: Therapy Invasive, Serious Disease • Roles not well defined for pediatrics: • Linezolid (Zyvox®): IV/PO, bacteriostatic in vitro (?not in vivo?) • Superior to vancomycin for treatment of adults with MRSA pneumonia (IDSA 2010 abstract) • Daptomycin (Cubicin®): rapidly bactericidal, but virtually NO pediatric data and NOT EFFECTIVE for pneumonia

27. Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Treatment for Skin / Skin Structure Infections (SSTI) • Oral antibiotics for Abscess/Cellulitis: • Clindamycin (if local strains susceptible) Staph + Strep [tastes bad] • TMP-SMX (Septra/Bactrim) Staph + ?Strep [no prospective, controlled studies vs clinda] • Doxycycline [bacteriostatic, for children older than 7 years] • Linezolid (Zyvox) Staph + Strep [expensive! Marrow toxicity for courses beyond 10 days]

28. All you need is drainage! Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Infect Dis J.2004;23(2):123-127.

29. CA-MRSA: Therapy of Mild – Moderate Infections How solid are the data supporting the use of TMP-SMX? …retrospective Retrospectivereview of convalescent therapy of MRSA infections (Baylor College of Medicine) Hyun DY, Mason EO, Forbes A, et al. Trimethoprim-sulfamethoxazole or clindamycin for treatment of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J. 2009;28(1):57-29.

30. CA-MRSA: Therapy of Mild – Moderate Infections A child with fever, induration or abscess, seen in the ED, has a 40% chance of failing TMP-SMX with infection presumed to be caused by MSSA, MRSA or Gp A strep Retrospective review of non-cultured, non-drained skin infections Elliott DJ, Zaoutis TE, Troxel AB, et al. Empiric antimicrobial therapy for pediatric skin and soft-tissue infections in the era of methicillin-resistant Staphylococcus aureus. Pediatrics. 2009;123(6):e959-e966.

31. CA-MRSA: Treatment for Skin / Skin Structure Infections (SSTI) • Minor skin infections (such as impetigo) and secondarily infected skin lesions (eg, eczema, ulcers, or lacerations): • Topical 2% mupirocin ointment • Cutaneous abscess: • Incision and drainage may be sufficient • Consider oral antibiotics for more severe cases • Cellulitis: Consider oral antibiotics Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

32. CA-MRSA: Bone and Joint Infections • Surgical debridement and drainage of associated soft tissue abscesses is the mainstay of therapy • Antibiotics intravenously: • Vancomycin • Antibiotics intravenous and oral: • Clindamycin • TMP-SMX 4 mg/kg/dose in combination with rifampin • Linezolid • Some experts recommend the addition of rifampin to IV or oral regimens Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

33. CA-MRSA: Bone and Joint Infections • The optimal duration of therapy for MRSA osteomyelitis is unknown: • A minimum of 4-6 weeks • An additional 1–3 months ( for chronic infection or if debridement is not performed) may be required • CRP (and/or ESR) may be helpful to guide response to therapy • Magnetic resonance imaging (MRI) with gadolinium is the imaging modality of choice for osteomyelitis Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

34. CA-MRSA: Bacteremia / Endocarditis • Vancomycin is recommended for the treatment of bacteremia and infective endocarditis • Duration of therapy may range from 2 to 6 weeks depending on source, presence of endovascular infection, and metastatic foci • Data regarding the safety and efficacy of alternative agents in children are limited; daptomycin may be an option • Clindamycin or linezolid may be considered in children whose bacteremia rapidly clears and is not related to an endovascular focus • Data are insufficient to support the routine use of combination therapy with rifampin or gentamicin in children with bacteremia or infective endocarditis; the decision to use combination therapy should be individualized Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

35. CA-MRSA: Decolonization for Recurrent SSTI • Decolonization may be considered in selected cases if • A patient develops a recurrent SSTI despite optimizing wound care and hygiene measures • Ongoing transmission is occurring despite optimizing wound care and hygiene measures • Decolonization strategies should be offered in conjunction with ongoing hygiene measures: • Nasal decolonization with mupirocin twice daily for 5–10 days with or withoutconcurrent topical body decolonization regimens with a skin antiseptic solution (eg, chlorhexidine*) for 5–14 days or dilute bleach baths • Oral antimicrobial therapy is not routinely recommended for decolonization *In San Diego, we use chlorhexidine every other day, or 3x/wk to decrease rates of recurrence Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38.

36. CA-MRSA in Sports

37. Current CA-MRSA: Pediatric Antibiotic Research • NIH/NICHD-sponsored trials of oral therapy/I&D for uncomplicated skin infections (clinda vs cephalexin vs TMP-SMX vs I&D) • Daptomycin is in pediatric clinical trials for complicated skin infections • Phase I PK studies ceftaroline, dalbavancin and torezolid

38. CA-MRSA: Summary • Respect CA-MRSA! • Vancomycin is still the preferred drug for invasive infection in children • Many new options are appearing for adults, not yet tested in children • Optimal dosing in children is not well defined • Clindamycin/TMP-SMX are reasonable options for mild/mod disease (little prospective data exist) • Whatever you use, do not automatically assume that the child will respond!

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